BRPI0608739A2 - composto, composição farmacêutica, uso de pelo menos um dos compostos, e, método para tratar distúrbios associados com um enfraquecimento do sistema imune - Google Patents

composto, composição farmacêutica, uso de pelo menos um dos compostos, e, método para tratar distúrbios associados com um enfraquecimento do sistema imune Download PDF

Info

Publication number: BRPI0608739A2
Authority: BR; Brazil
Prior art keywords: alkyl; fluorophenyl; phenyl; formula; pyridin
Prior art date: 2005-02-28

Application number

BRPI0608739-6A

Other languages

English (en)

Portuguese (pt)

Inventor

Cornelia Greim

Hans-Guenter Striegel

Karola Tollmann

Stefan Laufer

Wolfgang Albrecht

Philipp Merckle

Original Assignee

Merckle Gmbh

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2005-02-28

Filing date

2006-02-27

Publication date

2011-03-15

2006-02-27 Application filed by Merckle Gmbh filed Critical Merckle Gmbh

2011-03-15 Publication of BRPI0608739A2 publication Critical patent/BRPI0608739A2/pt

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 141
238000000034 method Methods 0.000 title claims abstract description 24
210000000987 immune system Anatomy 0.000 title claims abstract description 6
239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
208000035475 disorder Diseases 0.000 claims abstract description 5
230000002519 immonomodulatory effect Effects 0.000 claims abstract description 5
230000003313 weakening effect Effects 0.000 claims abstract description 4
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 149
-1 imidazole compound Chemical class 0.000 claims description 129
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 91
125000003118 aryl group Chemical group 0.000 claims description 90
125000000217 alkyl group Chemical group 0.000 claims description 74
229910052717 sulfur Inorganic materials 0.000 claims description 46
229910052760 oxygen Inorganic materials 0.000 claims description 43
125000001424 substituent group Chemical group 0.000 claims description 43
229910052736 halogen Inorganic materials 0.000 claims description 41
229910052739 hydrogen Inorganic materials 0.000 claims description 40
229910052799 carbon Inorganic materials 0.000 claims description 39
150000002367 halogens Chemical class 0.000 claims description 39
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 34
229910052757 nitrogen Inorganic materials 0.000 claims description 34
125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 29
150000003839 salts Chemical class 0.000 claims description 25
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 24
125000005843 halogen group Chemical group 0.000 claims description 24
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 24
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 21
125000005842 heteroatom Chemical group 0.000 claims description 21
125000003545 alkoxy group Chemical group 0.000 claims description 19
125000000753 cycloalkyl group Chemical group 0.000 claims description 19
125000006413 ring segment Chemical group 0.000 claims description 19
125000003282 alkyl amino group Chemical group 0.000 claims description 17
125000004414 alkyl thio group Chemical group 0.000 claims description 17
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 16
125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 15
125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 15
125000003277 amino group Chemical group 0.000 claims description 15
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
230000003287 optical effect Effects 0.000 claims description 10
125000006310 cycloalkyl amino group Chemical group 0.000 claims description 9
DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 9
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 7
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
125000005001 aminoaryl group Chemical group 0.000 claims description 5
125000003710 aryl alkyl group Chemical group 0.000 claims description 5
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
125000006766 (C2-C6) alkynyloxy group Chemical group 0.000 claims description 4
125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 4
125000004103 aminoalkyl group Chemical group 0.000 claims description 4
125000005188 oxoalkyl group Chemical group 0.000 claims description 4
125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 3
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 3
ADRUMUUMWYZKAN-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methylsulfinylimidazol-4-yl]-n-propan-2-ylpyridin-2-amine Chemical compound COCCN1C(S(C)=O)=NC(C=2C=CC(F)=CC=2)=C1C1=CC=NC(NC(C)C)=C1 ADRUMUUMWYZKAN-UHFFFAOYSA-N 0.000 claims description 2
239000000654 additive Substances 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
DRMJRHUMYBYDIX-UHFFFAOYSA-N n-[4-[5-(4-fluorophenyl)-3-methyl-2-methylsulfinylimidazol-4-yl]pyridin-2-yl]acetamide Chemical compound C1=NC(NC(=O)C)=CC(C=2N(C(=NC=2C=2C=CC(F)=CC=2)S(C)=O)C)=C1 DRMJRHUMYBYDIX-UHFFFAOYSA-N 0.000 claims description 2
125000005504 styryl group Chemical group 0.000 claims description 2
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
229920002554 vinyl polymer Polymers 0.000 claims description 2
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
125000004450 alkenylene group Chemical group 0.000 claims 1
125000005037 alkyl phenyl group Chemical group 0.000 claims 1
125000005124 aminocycloalkyl group Chemical group 0.000 claims 1
125000004429 atom Chemical group 0.000 claims 1
125000003884 phenylalkyl group Chemical group 0.000 claims 1
UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims 1
102000004127 Cytokines Human genes 0.000 abstract description 18
108090000695 Cytokines Proteins 0.000 abstract description 18
230000000694 effects Effects 0.000 abstract description 16
229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 abstract description 3
125000002883 imidazolyl group Chemical group 0.000 abstract description 2
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 119
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
229910052731 fluorine Inorganic materials 0.000 description 59
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 59
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 58
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 55
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
238000006243 chemical reaction Methods 0.000 description 49
239000000243 solution Substances 0.000 description 48
238000004128 high performance liquid chromatography Methods 0.000 description 45
239000000203 mixture Substances 0.000 description 44
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
238000005160 1H NMR spectroscopy Methods 0.000 description 40
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
235000019439 ethyl acetate Nutrition 0.000 description 39
239000011541 reaction mixture Substances 0.000 description 39
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 37
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
238000004440 column chromatography Methods 0.000 description 34
238000002360 preparation method Methods 0.000 description 34
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 32
238000007429 general method Methods 0.000 description 28
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 28
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 25
239000002244 precipitate Substances 0.000 description 24
239000000047 product Substances 0.000 description 24
238000005481 NMR spectroscopy Methods 0.000 description 23
238000012360 testing method Methods 0.000 description 23
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
239000002243 precursor Substances 0.000 description 21
239000000126 substance Substances 0.000 description 21
101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 20
239000002904 solvent Substances 0.000 description 20
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
239000002253 acid Substances 0.000 description 19
238000001816 cooling Methods 0.000 description 18
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
239000012043 crude product Substances 0.000 description 16
230000035484 reaction time Effects 0.000 description 16
239000000725 suspension Substances 0.000 description 16
NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 16
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 15
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
239000007858 starting material Substances 0.000 description 15
PPEHZPXBFQUZQY-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methylsulfanylimidazol-4-yl]pyridin-2-amine Chemical compound COCCN1C(SC)=NC(C=2C=CC(F)=CC=2)=C1C1=CC=NC(N)=C1 PPEHZPXBFQUZQY-UHFFFAOYSA-N 0.000 description 14
239000007787 solid Substances 0.000 description 14
125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 14
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 13
241001465754 Metazoa Species 0.000 description 13
239000013078 crystal Substances 0.000 description 13
238000003756 stirring Methods 0.000 description 13
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 13
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 13
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
238000002290 gas chromatography-mass spectrometry Methods 0.000 description 12
150000003462 sulfoxides Chemical class 0.000 description 12
XUXJHBAJZQREDB-UHFFFAOYSA-N 2-methylbutanamide Chemical compound CCC(C)C(N)=O XUXJHBAJZQREDB-UHFFFAOYSA-N 0.000 description 11
230000005764 inhibitory process Effects 0.000 description 11
239000011734 sodium Substances 0.000 description 11
229910052681 coesite Inorganic materials 0.000 description 10
229910052906 cristobalite Inorganic materials 0.000 description 10
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
230000003647 oxidation Effects 0.000 description 10
238000007254 oxidation reaction Methods 0.000 description 10
JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 10
229910052682 stishovite Inorganic materials 0.000 description 10
238000004809 thin layer chromatography Methods 0.000 description 10
229910052905 tridymite Inorganic materials 0.000 description 10
125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
108060008682 Tumor Necrosis Factor Proteins 0.000 description 9
102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 9
230000015572 biosynthetic process Effects 0.000 description 9
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 9
IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 9
FGKJLKRYENPLQH-UHFFFAOYSA-N isocaproic acid Chemical compound CC(C)CCC(O)=O FGKJLKRYENPLQH-UHFFFAOYSA-N 0.000 description 9
239000000463 material Substances 0.000 description 9
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 8
150000001412 amines Chemical class 0.000 description 8
QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
239000000460 chlorine Substances 0.000 description 8
PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 8
239000007789 gas Substances 0.000 description 8
238000010438 heat treatment Methods 0.000 description 8
WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 8
238000010992 reflux Methods 0.000 description 8
125000003396 thiol group Chemical class [H]S* 0.000 description 8
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
210000004369 blood Anatomy 0.000 description 7
239000008280 blood Substances 0.000 description 7
238000002451 electron ionisation mass spectrometry Methods 0.000 description 7
238000002474 experimental method Methods 0.000 description 7
150000002460 imidazoles Chemical class 0.000 description 7
239000000543 intermediate Substances 0.000 description 7
239000012074 organic phase Substances 0.000 description 7
239000012071 phase Substances 0.000 description 7
238000000746 purification Methods 0.000 description 7
238000001953 recrystallisation Methods 0.000 description 7
230000002829 reductive effect Effects 0.000 description 7
238000006467 substitution reaction Methods 0.000 description 7
150000003457 sulfones Chemical class 0.000 description 7
OVJCNVBXRABLOR-UHFFFAOYSA-N 6-(4-fluorophenyl)-5-(2-fluoropyridin-4-yl)-2,3-dihydroimidazo[2,1-b][1,3]thiazole Chemical compound C1=CC(F)=CC=C1C1=C(C=2C=C(F)N=CC=2)N2CCSC2=N1 OVJCNVBXRABLOR-UHFFFAOYSA-N 0.000 description 6
102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 6
108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 6
102000001253 Protein Kinase Human genes 0.000 description 6
230000003110 anti-inflammatory effect Effects 0.000 description 6
238000004587 chromatography analysis Methods 0.000 description 6
239000011737 fluorine Substances 0.000 description 6
239000005457 ice water Substances 0.000 description 6
230000002401 inhibitory effect Effects 0.000 description 6
239000003921 oil Substances 0.000 description 6
239000007800 oxidant agent Substances 0.000 description 6
210000002381 plasma Anatomy 0.000 description 6
239000000741 silica gel Substances 0.000 description 6
229910002027 silica gel Inorganic materials 0.000 description 6
229910000104 sodium hydride Inorganic materials 0.000 description 6
LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
IOXAEZSQRZMYNX-UHFFFAOYSA-N 1-(2-aminopyridin-4-yl)-2-(4-fluorophenyl)ethanone Chemical compound C1=NC(N)=CC(C(=O)CC=2C=CC(F)=CC=2)=C1 IOXAEZSQRZMYNX-UHFFFAOYSA-N 0.000 description 5
CZNCQAVWOBBVMF-UHFFFAOYSA-N 2-(4-fluorophenyl)-1-(2-fluoropyridin-4-yl)ethanone Chemical compound C1=CC(F)=CC=C1CC(=O)C1=CC=NC(F)=C1 CZNCQAVWOBBVMF-UHFFFAOYSA-N 0.000 description 5
NEDLYQXZCPTKOD-UHFFFAOYSA-N 2-methyl-3-phenylpropanamide Chemical compound NC(=O)C(C)CC1=CC=CC=C1 NEDLYQXZCPTKOD-UHFFFAOYSA-N 0.000 description 5
229910004809 Na2 SO4 Inorganic materials 0.000 description 5
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
239000004480 active ingredient Substances 0.000 description 5
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 5
239000003480 eluent Substances 0.000 description 5
239000000284 extract Substances 0.000 description 5
238000001914 filtration Methods 0.000 description 5
239000003112 inhibitor Substances 0.000 description 5
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 5
108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 5
108060006633 protein kinase Proteins 0.000 description 5
GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 5
VNQIEKXUBYBTPS-UHFFFAOYSA-N 2-acetamidopyridine-4-carboxylic acid Chemical compound CC(=O)NC1=CC(C(O)=O)=CC=N1 VNQIEKXUBYBTPS-UHFFFAOYSA-N 0.000 description 4
LDUCTLWCKOLAPM-UHFFFAOYSA-N 2-methyl-1h-pyridin-2-amine Chemical compound CC1(N)NC=CC=C1 LDUCTLWCKOLAPM-UHFFFAOYSA-N 0.000 description 4
JOZZAIIGWFLONA-UHFFFAOYSA-N 3-methylbutan-2-amine Chemical compound CC(C)C(C)N JOZZAIIGWFLONA-UHFFFAOYSA-N 0.000 description 4
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
108010044467 Isoenzymes Proteins 0.000 description 4
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
150000007513 acids Chemical class 0.000 description 4
230000010933 acylation Effects 0.000 description 4
238000005917 acylation reaction Methods 0.000 description 4
PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
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238000010828 elution Methods 0.000 description 4
239000002158 endotoxin Substances 0.000 description 4
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XIUFWXXRTPHHDQ-UHFFFAOYSA-N prop-1-ene;1,1,2,2-tetrafluoroethene Chemical group CC=C.FC(F)=C(F)F XIUFWXXRTPHHDQ-UHFFFAOYSA-N 0.000 description 1
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
150000003180 prostaglandins Chemical class 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
208000005069 pulmonary fibrosis Diseases 0.000 description 1
125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
125000003226 pyrazolyl group Chemical group 0.000 description 1
ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
230000009467 reduction Effects 0.000 description 1
QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
208000037803 restenosis Diseases 0.000 description 1
206010039073 rheumatoid arthritis Diseases 0.000 description 1
238000005488 sandblasting Methods 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
150000003335 secondary amines Chemical class 0.000 description 1
230000036303 septic shock Effects 0.000 description 1
230000019491 signal transduction Effects 0.000 description 1
229910000077 silane Inorganic materials 0.000 description 1
238000005245 sintering Methods 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
235000019333 sodium laurylsulphate Nutrition 0.000 description 1
239000011343 solid material Substances 0.000 description 1
239000007921 spray Substances 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
238000003860 storage Methods 0.000 description 1
230000035882 stress Effects 0.000 description 1
235000000346 sugar Nutrition 0.000 description 1
150000008163 sugars Chemical class 0.000 description 1
150000003871 sulfonates Chemical class 0.000 description 1
QJEXFQIDEHSWNM-UHFFFAOYSA-N sulfonylmethane hydrochloride Chemical compound Cl.C=S(=O)=O QJEXFQIDEHSWNM-UHFFFAOYSA-N 0.000 description 1
235000011149 sulphuric acid Nutrition 0.000 description 1
239000000375 suspending agent Substances 0.000 description 1
201000000596 systemic lupus erythematosus Diseases 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
230000006433 tumor necrosis factor production Effects 0.000 description 1
210000000689 upper leg Anatomy 0.000 description 1
235000012141 vanillin Nutrition 0.000 description 1
MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
229940117960 vanillin Drugs 0.000 description 1
206010047470 viral myocarditis Diseases 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Veterinary Medicine (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Immunology (AREA)
Neurosurgery (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Physical Education & Sports Medicine (AREA)
Rheumatology (AREA)
Orthopedic Medicine & Surgery (AREA)
Diabetes (AREA)
Pain & Pain Management (AREA)
Virology (AREA)
Heart & Thoracic Surgery (AREA)
Communicable Diseases (AREA)
Oncology (AREA)
Cardiology (AREA)
Obesity (AREA)
Psychiatry (AREA)
Tropical Medicine & Parasitology (AREA)
AIDS & HIV (AREA)
Emergency Medicine (AREA)
Endocrinology (AREA)
Hematology (AREA)
Transplantation (AREA)
Hospice & Palliative Care (AREA)
Molecular Biology (AREA)
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BRPI0608739-6A 2005-02-28 2006-02-27 composto, composição farmacêutica, uso de pelo menos um dos compostos, e, método para tratar distúrbios associados com um enfraquecimento do sistema imune BRPI0608739A2 (pt)

Applications Claiming Priority (5)

Application Number	Priority Date	Filing Date	Title
US65638905P	2005-02-28	2005-02-28
EP05004369.4		2005-02-28
US60/656,389		2005-02-28
EP05004369		2005-02-28
PCT/EP2006/001801 WO2006089798A1 (en)	2005-02-28	2006-02-27	2-sulfinyl- and 2-sulfonyl-substituted imidazole derivatives and their use as cytokine inhibitors

Publications (1)

Publication Number	Publication Date
BRPI0608739A2 true BRPI0608739A2 (pt)	2011-03-15

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BRPI0608739-6A BRPI0608739A2 (pt)	2005-02-28	2006-02-27	composto, composição farmacêutica, uso de pelo menos um dos compostos, e, método para tratar distúrbios associados com um enfraquecimento do sistema imune

Country Status (20)

Country	Link
US (1)	US20100273833A1 (de)
EP (1)	EP1853581B1 (de)
JP (1)	JP2008531627A (de)
KR (1)	KR20070107082A (de)
CN (1)	CN101128453A (de)
AT (1)	ATE469893T1 (de)
AU (1)	AU2006218037B2 (de)
BR (1)	BRPI0608739A2 (de)
CA (1)	CA2599449A1 (de)
DE (1)	DE602006014657D1 (de)
DK (1)	DK1853581T3 (de)
ES (1)	ES2351308T3 (de)
IL (1)	IL184745A0 (de)
MX (1)	MX2007010496A (de)
NO (1)	NO20074912L (de)
NZ (1)	NZ560264A (de)
PT (1)	PT1853581E (de)
RU (1)	RU2007135955A (de)
WO (1)	WO2006089798A1 (de)
ZA (1)	ZA200708203B (de)

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EP1894925A1 (de) *	2006-08-24	2008-03-05	Merckle Gmbh	Imidazol Derivate mit entzündungshemmender Wirkung
US8143294B2 (en)	2007-12-31	2012-03-27	Michael Burnet	2-sulfanyl-substituted imidazole derivatives and their use as cytokine inhibitors
CN102249992A (zh) *	2011-07-05	2011-11-23	广东工业大学	一种制备2-氨基异烟酸的方法
US20190060286A1 (en)	2016-02-29	2019-02-28	University Of Florida Research Foundation, Incorpo	Chemotherapeutic Methods
NZ762856A (en)	2017-10-05	2020-07-31	Fulcrum Therapeutics Inc	P38 kinase inhibitors reduce dux4 and downstream gene expression for the treatment of fshd
US10342786B2 (en)	2017-10-05	2019-07-09	Fulcrum Therapeutics, Inc.	P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11795160B2 (en) *	2019-02-22	2023-10-24	Insilico Medicine Ip Limited	Kinase inhibitors
AU2022225035A1 (en)	2021-02-24	2023-08-31	Insilico Medicine Ip Limited	Analogs for the treatment of disease

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GB9713726D0 (en) *	1997-06-30	1997-09-03	Ciba Geigy Ag	Organic compounds
CA2295021A1 (en) *	1997-06-30	1999-01-28	Ortho-Mcneil Pharmaceutical, Inc.	2-substituted imidazoles useful in the treatment of inflammatory diseases
JP2003503456A (ja) *	1999-07-02	2003-01-28	スチュアートエイ．リプトン	神経傷害またはアポトーシスを軽減する方法
DE10107683A1 (de) *	2001-02-19	2002-08-29	Merckle Gmbh Chem Pharm Fabrik	2-Thio-substituierte Imidazolderivate und ihre Verwendung in der Pharmazie
DE10114775A1 (de) *	2001-03-26	2002-10-10	Gerhard Dannhardt	2-Mercapto-4,5-diarylimidazolderivate und ihre Verwendung in der Pharmazie
KR20020009532A (ko) *	2001-11-13	2002-02-01	(주)쎌믹스	류코트리엔 합성 억제용 조성물
DE10222103A1 (de) *	2002-05-17	2003-11-27	Merckle Gmbh Chem Pharm Fabrik	2-Thio-substituierte Imidazolderivate und ihre Verwendung in der Pharmazie
DE10238045A1 (de) *	2002-08-20	2004-03-04	Merckle Gmbh Chem.-Pharm. Fabrik	2-Thio-substituierte Imidazolderivate und ihre Verwendung in der Pharmazie

2006
- 2006-02-27 CA CA002599449A patent/CA2599449A1/en not_active Abandoned
- 2006-02-27 PT PT06723133T patent/PT1853581E/pt unknown
- 2006-02-27 EP EP06723133A patent/EP1853581B1/de not_active Expired - Lifetime
- 2006-02-27 BR BRPI0608739-6A patent/BRPI0608739A2/pt not_active IP Right Cessation
- 2006-02-27 ES ES06723133T patent/ES2351308T3/es not_active Expired - Lifetime
- 2006-02-27 AU AU2006218037A patent/AU2006218037B2/en not_active Ceased
- 2006-02-27 JP JP2007557404A patent/JP2008531627A/ja active Pending
- 2006-02-27 CN CNA2006800062247A patent/CN101128453A/zh active Pending
- 2006-02-27 KR KR1020077019748A patent/KR20070107082A/ko not_active Ceased
- 2006-02-27 MX MX2007010496A patent/MX2007010496A/es not_active Application Discontinuation
- 2006-02-27 DE DE602006014657T patent/DE602006014657D1/de not_active Expired - Lifetime
- 2006-02-27 RU RU2007135955/04A patent/RU2007135955A/ru not_active Application Discontinuation
- 2006-02-27 WO PCT/EP2006/001801 patent/WO2006089798A1/en not_active Ceased
- 2006-02-27 US US11/817,298 patent/US20100273833A1/en not_active Abandoned
- 2006-02-27 AT AT06723133T patent/ATE469893T1/de not_active IP Right Cessation
- 2006-02-27 DK DK06723133.2T patent/DK1853581T3/da active
- 2006-02-27 NZ NZ560264A patent/NZ560264A/en not_active IP Right Cessation
2007
- 2007-07-19 IL IL184745A patent/IL184745A0/en unknown
- 2007-09-26 ZA ZA200708203A patent/ZA200708203B/xx unknown
- 2007-09-27 NO NO20074912A patent/NO20074912L/no not_active Application Discontinuation

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Publication number	Publication date
EP1853581B1 (de)	2010-06-02
EP1853581A1 (de)	2007-11-14
CA2599449A1 (en)	2006-08-31
NZ560264A (en)	2009-11-27
US20100273833A1 (en)	2010-10-28
DE602006014657D1 (de)	2010-07-15
ATE469893T1 (de)	2010-06-15
AU2006218037B2 (en)	2012-04-05
ES2351308T3 (es)	2011-02-02
IL184745A0 (en)	2007-12-03
NO20074912L (no)	2007-11-28
WO2006089798A1 (en)	2006-08-31
ZA200708203B (en)	2008-10-29
CN101128453A (zh)	2008-02-20
JP2008531627A (ja)	2008-08-14
KR20070107082A (ko)	2007-11-06
PT1853581E (pt)	2010-09-09
MX2007010496A (es)	2007-11-07
DK1853581T3 (da)	2010-09-27
RU2007135955A (ru)	2009-04-10
AU2006218037A1 (en)	2006-08-31

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2012-06-05	B08F	Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]	Free format text: REFERENTE A 6A ANUIDADE.
2012-10-23	B08K	Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]	Free format text: REFERENTE AO DESPACHO 8.6 PUBLICADO NA RPI 2161 DE 05/06/2012.

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